Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most heavily consumed pharmaceuticals due to their great efficacy to reduce fever, pain and inflammation but are frequently associated with GI side- effects such as peptic ulceration and bleeding. We have been encouraged by the results obtained in Phase I, and the present proposal outlines a number of critical studies which are required to develop a family of NSAID-phospholipid prodrugs which chronically protect rats from the GI toxicity of NSAIDs while maintaining or enhancing their therapeutic activity. Our preliminary studies also revealed that the potency of phospholipid-associated aspirin to inhibit cyclooxygenase-2 (COX) appeared to be enhanced in comparison to unmodified aspirin in activated endothelial cells. We have proposed biochemical studies to examine the inhibitory effects of the NSAID test-formulations on the COX isoenzymes of cells derived from GI mucosa and other tissues. We also propose analytical and spectroscopic studies to provide insight into the mechanisms by which NSAIDs chemically associate with zwitterionic phospholipids and their effects on both the shelf-life and biological half-life of NSAIDs. We believe that the proposed studies will yield cost-effective formulations of NSAIDs with phospholipids that besides high therapeutic activity will have very low to negligible GI toxicity. PROPOSED COMMERCIAL APPLICATIONS: Peptic ulcer disease and gastrointestinal (GI) bleeding represent the major complication of individuals consuming NSAIDs for the relief of pain, fever and inflammation. Indeed 40-50% of arthritics that are dependent on these drugs for relief of pain and inflammation have a GI intolerance to aspirin and other NSAIDs. The market for GI-safe NSAIDs with enhanced therapeutic activity, which appear to be characteristics of the NSAID-phospholipid prodrugs, would be enormous.